To Örebro University

BACKGROUND: Riedel´s thyroiditis (RT) is a rare inflammatory disease of the thyroid gland, causing compression and fibrosis of adjacent tissues. Typically the goiter is hard and firm. Hoarseness, dyspnea, and dysphagia may be present.

METHODS: We retrospectively reviewed all patients known by us with RT in addition to all patients with appropriate ICD-10 codes evaluated at the Karolinska University Hospital 2003-2015. Clinical, biochemical, and histological data of patients with RT were recorded in detail. Histological preparations were re-examined when available.

RESULTS: RT was diagnosed in six patients. Five were females and the median age at first presentation was 50 years (25-81 years). Median follow-up time was 3.75 years (1-22 years). At diagnosis five had hypothyroidism. Four had extrathyroidal manifestations, and one of these had also distant fibrosis. One patient had a clear IgG4/IgG ratio over 40%. One patient was treated with tracheostomy, one with isthmectomy and one with total thyroidectomy. Four had been treated with glucocorticoids, four with tamoxifen, and two with both drugs. One had also been treated with mycophenolate mofetil combined with Rituximab. At the end of follow-up four was doing fine, one had recurrent episodes of inflammation and one had died of possible complications to RT.

CONCLUSION: It is important to recognize RT and give adequate treatment. Steroids are still the mainstay of therapy but other medications against fibrosclerosis can be considered. Wakefulness of other fibrosing manifestations is essential. Immunohistochemistry can show whether IgG-4 plasma cells are increased which could lead to fibrosis in other organs.

Vitamin D has received much attention in recent years due to the re-emergence of vitamin D deficiency as a global health issue along with increasing evidence indicating that 1,25-dihydroxivitamin D, the hormonally active form of vita-min D, not only acts in calcium and bone metabolism but also generates ex-traskeletal biological responses.

In this thesis, the role of vitamin D in obesity and other associated condi-tions has been studied.

In paper 1, the prevalence of vitamin D deficiency and secondary hyperpara-thyroidism over the long term after Roux-en-Y gastric bypass (RYGB) were evaluated. We found a substantial prevalence of vitamin D deficiency and secondary hyperparathyroidism after RYGB, whereas calcium levels remained within normal range. An expected improvement in vitamin D status after weight loss could have been countered by the malabsorption induced by surgery.

In paper 2, the prevalence of anemia and related deficiencies over the long term after RYGB were studied. We found that 27% of the patients had anemia postoperatively, 20% had iron deficiency, 12% had folate deficiency and 2% had vitamin B12 deficiency. Anemia was mainly due to iron deficiency, and its frequency did not seem to progress with time after surgery.

In paper 3, the effects of vitamin D supplementation on body composition and cardiorespiratory fitness in overweight men with vitamin D deficiency at baseline were investigated. No statistically significant difference between the placebo and the intervention group regarding changes in percentage body fat, maximum oxygen uptake, BMI and maximum load was found.

In paper 4, the prevalence and determinants of 3-epi-25(OH)D3 were exam-ined. 3-epi-25(OH)D3 was detected in 7.7% of the study population and the mean concentration was 8.4 nmol/L. The quantification of 3-epi-25(OH)D3 would not significantly influence the clinical interpretation of vitamin D levels.

In conclusion, new knowledge about vitamin D is continuously emerging but there is a discrepancy between cross-sectional studies associating low vitamin D levels to obesity and other related metabolic complications and the lack of effects of vitamin D supplementation in clinical trials. Large RCTs with longer duration in obese subjects with baseline vitamin D deficiency are warranted.

Background: The discovery of an epimeric form of 25(OH)D3 may complicate the interpretation of vitamin Dstatus. The aim of this study was to examine the prevalence and determinants of 25-hydroxy-3-epi-vitamin D3 (3- epi-25(OH)D3) in a mid-Swedish region and to investigate how the measurement of 3-epi-25(OH)D3 would affect the assessment of vitamin D status using current thresholds.

Methods: We conducted a cross-sectional study of 8286 in- and outpatients in primary as well as secondary care settings. Plasma 25(OH)D, 25(OH)D2, 25(OH)D3 and 3-epi-25(OH)D3 were measured using High Pressure Liquid Chromatography – Tandem Mass Spectrometry (HPLC – MS/MS). The relative 3-epi-25(OH)D3 contribution was calculated as a percentage of the total 25(OH)D3. Blood samples were collected between March 2014 and July 2015 providing a seasonal aspect to the results.

Results: 3-epi-25(OH)D3was detected in 635 cases (7.7% of all subjects), and the mean concentration was8.4 ± 3.5 nmol/L. 3-epi-25(OH)D3correlated significantly with 25(OH)D3(r =0.38, p < 0.001).A multivariateanalysis among the detected showed that male gender and winter season were independently associatedwith higher 3-epi-25(OH)D3/25(OH)D3percentage ratio (R2=0.044). Infants and children had a significantlyhigher detection rate compared to the reference age category (18–45 years) as well as those who were testedduring the summer season.

Conclusions: We report findings from the first epidemiologic study of 3-epi-25(OH)D3 conducted in Sweden, based on a large population sample. 3-epi-25(OH)D3 was detected in 7.7% of the study population and the mean concentration was 8.4 nmol/L. The quantification of 3-epi-25(OH)D3 would not significantly influence the clinical interpretation of vitamin D levels. Additional studies are needed to understand the metabolic pathway and the possible physiological functions of this metabolite.

Bariatric surgery has gained wide acceptance as treatment for severe obesity and is associated with decreased overall mortality. The aims of this study were to evaluate the prevalence of anemia long term after Roux-en-Y gastric bypass (RYGB) and to search for factors predicting anemia.

All 745 patients who underwent RYGB between 1993 and 2003 at either A-rebro or Uppsala University Hospital and who were living in Sweden were invited to participate by providing a fasting blood sample and completing a questionnaire about their health status. Full blood count, serum iron, transferrin, vitamin B-12, and folic acid were determined.

Follow-up was completed in 431 patients (58 %) with mean age 51.3 +/- 10 years. Of all patients, 27 % had anemia postoperatively and related deficiencies; iron, folic acid, and vitamin B-12 were seen in 20, 12, and 2 %, respectively. There was no correlation between anemia and sex, follow-up time, 25-OH vitamin D level, and preoperative or postoperative BMI. An inverse correlation was found between anemia and regular medical checkups concerning gastric bypass surgery.

Twenty-seven percent of patients had anemia more than 10 years after RYGB. Anemia does not seem to progress with time and was less common in patients with regular medical checkups. Thus, improved long-term follow-up is needed.

The primary aim of this study was to evaluate the prevalence of vitamin D deficiency and secondary hyperparathyroidism after Roux-en-Y gastric bypass. Secondly, we have tried to assess predictors for vitamin D deficiency. Five hundred thirty-seven patients who underwent primary Roux-en-Y gastric bypass surgery between 1993 and 2003 at the A-rebro University Hospital and Uppsala University Hospital were eligible for the study. Patients were asked to provide a blood sample between November 2009 and June 2010 and to complete a questionnaire about their postoperative health status. Serum values of 25-OH vitamin D, parathyroid hormone (PTH), alkaline phosphatase (ALP) and calcium were determined. Follow-up was completed in 293 patients, of which 83 % were female, with an age of 49 +/- 9.9 years after a median time of 11 +/- 2.8 years. Vitamin D, PTH and albumin-corrected calcium values were 42 +/- 20.4 nmol/L, 89.1 +/- 52.7 ng/L and 2.3 +/- 0.1 mmol/L, respectively. Of all patients, 65 % were vitamin D deficient, i.e. 25-OH vitamin D < 50 nmol/L, and 69 % had PTH above the upper normal reference range, i.e. > 73 ng/L. Vitamin D was inversely correlated with PTH levels (p < 0.001) and positively correlated with calcium (p = 0.016). Vitamin D did not correlate with ALP. The only factor found to predict vitamin D deficiency was high preoperative body mass index (BMI) (p = 0.008), whereas gender, age, time after surgery and BMI at follow-up did not. Vitamin D deficiency and secondary hyperparathyroidism after Roux-en-Y gastric bypass (RYGB) were confirmed in our study because 65 % of patients had vitamin D deficiency, and 69 % had increased PTH levels more than 10 years after surgery. These data are alarming and highlight the need for improved long-term follow-up. Vitamin D deficiency does not seem to progress with time after surgery, possibly due to weight loss. Only preoperative BMI, cutoff point 43 kg/m(2), was a predictor of vitamin D deficiency at follow-up. Improved long-term follow-up of patients that undergo RYGB is needed.